PHASE 1, 2, or 1/2
LETTER OF INTENT
Submission Form v7.1
National Cancer Institute
Division of Cancer Treatment and Diagnosis
Cancer Therapy Evaluation Program
To complete the form electronically, use the mouse pointer or the Tab key to navigate. Select and enter text for each text field.
Lead Group/Institution: [Click and enter Lead Group/Institution]
Lead Group/Institution Code1: [Click and enter Lead Group/Institution Code]
Other Trial Team Sites1: [Click and enter Other Clinical Sites/Institution Codes; list sites outside USA
separately by country]
[Click and enter Translational Sites]
Title of LOI : [Click here to enter Title]
LOI Version Submission Date: [Click here to enter Date of submission to PIO]
CTEP IND Agent(s)/(supplied by NCI)1: [Click and enter CTEP IND Agent]
CIP IND Imaging Agent(s)/Supplier: [Click and enter CIP IND Imaging Agent(s)] [Click here to enter Supplier]
Non-NCI IND Agent(s)/Supplier: [Click and enter Non-NCI IND Agent(s)] [Click and enter Supplier]
Commercial Agent(s)/Source: [Click here to enter Commercial Agents] [Click and enter Source]
Tumor Type: [[ ]] Solid Tumor
(Click within the [[ ]] and type ‘x’ to indicate the
tumor type)
[[ ]] Hematologic Malignancy (NOS)
[[ ]] Disease-Specific
Disease-Specific1: 1. [Click and enter Disease Name] [Click and enter Disease Code]
(Specify the Name and Code of the Study
Disease)
2. [Click and enter Disease Name] [Click and enter Disease Code]
3. [Click and enter Disease Name] [Click and enter Disease Code]
Phase of Study: [Click and enter Study Phase]
Estimated Monthly Accrual: [Click and enter Accrual]
(Note: Projected accrual rates should be realistic.
Actual accrual will be monitored and measured
against this accrual estimate, and failure to meet
accrual goals may result in study closure. )
Proposed Sample Size: Minimum: [Click and enter Size] Maximum: [Click and enter Size]
Earliest date the study can begin: [Click and enter Date]
Projected Accrual Dates: Document in Appendix A.
Is this study as a whole part of an NIH Grant, [Click and enter Y or N]
Cooperative Agreement or Contract?
If yes, provide the Award Number: [Click and enter Award Number]
1
Detailed Institution, Group, Agent NSC, and Disease codes are available on the CTEP Home Page at
http://ctep.cancer.gov/protocolDevelopment/codes_values.htm
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LOI Submission Form
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Will this study as a whole receive support [Click and enter Y or N]
from non-NCI sources (i.e., industry,
foundations)?
If yes, indicate the source of the funding: [Click and enter source of non-NCI funding]
If no, will non-NCI funding be sought? [Click and enter Y or N]
Will an investigational laboratory assay be [Click and enter Y or N]
used as an integral biomarker in the trial?2
If yes, indicate all integral investigational [Click and enter name of each integral biomarker and describe purpose and other
laboratory assay(s) and the purpose(s) for details in Correlates table below]
each one: e.g., eligibility criterion,
assignment to treatment, stratification
variable, risk classifier or score, other
(describe in detail).2
(If the investigational assay(s) is used for
medical decision-making [or treatmentdirecting], then this LOI and supporting
documentation may be forwarded to the
Office of In Vitro Diagnostics and
Radiological Health (OIR)/FDA for review. If
the assay(s) has/have already been
presented to OIR/FDA, then please denote.)
If the proposed trial includes correlative [Click and enter Y or N]
studies, indicate whether there is currently
funding for them.
If yes, provide funding source for each [List correlatives and provide funding source (e.g., grant number if applicable) for
correlative study. If funding is available for each]
some, but not all, correlatives, please
indicate.
If no, will funding for correlative studies be [Click and enter Y or N]
sought?
Is this a Career Development LOI? [Click and enter Y or N]
Further information and instructions regarding the submission of a Career
Development LOI may be found at
http://ctep.cancer.gov/protocolDevelopment/letter_of_intent.htm#instructions
If yes, please attach and check off the PI curriculum vitae [[ ]]
following: Institutional letter of commitment [[ ]]
Mentor letter of commitment [[ ]]
2
An investigational laboratory assay is one that has not been cleared or approved by the FDA for the purpose for which it will be used in this
trial. See the Correlates section of this form for definitions of “integral” and “integrated” biomarkers.
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LOI Submission Form
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The Investigational Drug Steering Committee (IDSC) is designed to provide NCI with broad external scientific and clinical input
for the design and prioritization of phase 1 and phase 2 trials with agents for which CTEP holds an IND.
Membership of the IDSC includes the Principal Investigators of early phase drug development grants and contracts, representatives
from the NCI National Clinical Trials Network (NCTN), NCI staff members, and additional representatives with expertise in
biostatistics, correlative science technologies, radiation oncology, etc., as well as patient advocates and community oncologists, as
needed. Individuals with special expertise will be included as ad hoc members for consideration of specific agents. The current
membership list may be found at http://transformingtrials.cancer.gov/steering-committees/investigational-drug.
Periodically the IDSC will assess LOIs from a strategic perspective to determine whether the Clinical Development Plan for an agent
should be modified. When requested by CTEP, the IDSC will provide input on LOIs to assist in CTEP decision-making. Information
in a LOI assessed by IDSC is kept confidential and members with potential conflict of interest are recused from participating in the
LOI assessment. The IDSC strategic assessment is not part of the CTEP LOI review process and will not affect LOI review
timelines. All LOIs in request for a Project Team Member Application or other solicitation may receive IDSC review.
For unsolicited LOIs only: Please check one of the following options (Note: While selecting an option is required, neither choice will
affect the outcome of the CTEP review of this LOI):
This LOI may [[ ]] /may not [[ ]] be looked at by the IDSC.
Note: If the LOI is disapproved by CTEP, the Principal Investigator may appeal the decision by requesting a review by the IDSC.
Principal Investigator (PI) Name: [Click and type Your Full Name to certify the
submission]
Date:
[Click and enter Date]
Date:
[Click and enter Date]
Date:
[Click and enter Date]
Date:
[Click and enter Date]
PI Street Address: [Click and enter Room/Suite/Dept.]
[Click and enter Street Address]
[Click and enter City, State, Postal Code]
PI Phone: [Click and enter Phone No.]
PI Fax: [Click and enter Fax No.]
PI E-mail: [Click and enter E-mail Address]
Study Statistician Name: [Click and type Your Full Name to certify the
submission]
Statistician Address: [Click and enter Room/Suite/Dept.]
[Click and enter Street Address]
[Click and enter City, State, Postal Code]
Statistician Phone: [Click and enter Phone No.]
Statistician Fax: [Click and enter Fax No.]
Statistician E-mail: [Click and enter E-mail Address]
Grant or Contract-PI Name: [Click and type Your Full Name to certify the
submission]
Grant or Contract-PI Address: [Click and enter Room/Suite/Dept.]
[Click and enter Street Address]
[Click and enter City, State, Postal Code]
Grant or Contract-PI Phone: [Click and enter Phone No.]
Grant or Contract-PI Fax: [Click and enter Fax No.]
Grant or Contract-PI E-mail: [Click and enter E-mail Address]
Group Chair-PI (GC-PI) Name: [Click and type Your Full Name to certify the
submission]
GC-PI Address: [Click and enter Room/Suite/Dept.]
[Click and enter Street Address]
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LOI Submission Form
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[Click and enter City, State, Postal Code]
GC-PI Phone: [Click and enter Phone No.]
GC-PI Fax: [Click and enter Fax No.]
GC-PI E-mail: [Click and enter E-mail Address]
Please submit LOIs to the Protocol Information Office (PIO) via e-mail at:
pio@ctep.nci.nih.gov, Attention: LOI Coordinator
Notes:
LOIs from a NCTN Group must be submitted through the Group Operations.
Proposals for trials to be conducted under a Cooperative Agreement must include complete contact information for the
Principal Investigator and Protocol Chair.
Questions? Please e-mail the LOI Coordinator at pio@ctep.nci.nih.gov.
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LOI Submission Form
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Rationale and Background: (This section should provide the study rationale and supporting preclinical and/or clinical data and
address the following: what is the unmet need, why the patient population was chosen, why the drug or drug combination was
chosen and any potential safety concerns with the drugs or drug combination, and how the study results might impact future
trials/practice. The background information should be limited to what is relevant to the proposed study and should be presented
succinctly but with sufficient detail to enable evaluation by the reviewers. Avoid indiscriminate cutting-and-pasting from investigator
brochures, trial solicitations, or other CTEP communications.)
[Click and enter Background]
Hypotheses: (Succinctly state the hypothesis for each primary and secondary objective.)
[Click and enter Rationale/Hypotheses]
Objectives: (List primary and secondary objectives. Ensure that the study design allows for these objectives to be met and that the
statistical plan provides an adequate plan to analyze or describe the data for each objective.)
[Click and enter Objectives]
Abbreviated Eligibility Criteria: (Provide key inclusion criteria. These should include patient age, performance status, whether
abnormal organ function is permitted [if Yes, list only abnormal organ function parameters], permissible and required prior therapy,
tumor type, and integral markers, if applicable.)
[Click and enter Eligibility Criteria]
Study Design: (Succinctly describe the general study design. If applicable, describe randomization and/or stratification. A schema
or flow diagram may be used, if appropriate. If the trial involves biomarker studies, the Biomarkers Table below must be filled out
according to the instructions. Appendices detailing the biomarker assays may be required as well. Please read the instructions
carefully.)
[Click and enter Study Design]
Treatment Plan: (State the dose, method of administration, and schedule of each drug, and, if phase 1, provide the dose
escalation scheme, and definitions of DLTs. State the duration of treatment, the duration of the study, and the duration of follow-up.)
[Click and enter Plan]
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LOI Submission Form
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Correlates: For all correlates, whether integral, integrated, or exploratory, and whether or not CTEP support will be requested,
provide text in an appendix describing them and complete the Biomarkers Table below. Refer to footnote, page 2, for
definitions of integral and integrated biomarker tests. All other biomarker tests are considered exploratory. In the table, provide
the name of the lead PI for each correlate and his/her site. In the column labeled “M/O”, indicate with “M” or “O” if specimen
collection or imaging test is either Mandatory or Optional. If the assay result will be reported to the patient or the patient’s
physician at any time, on or off study, the assay must be performed at a CLIA-approved laboratory. For all correlates, provide a
letter of commitment from the collaborating laboratory.
An integral biomarker is one that is inherent to the design of the trial and must be measured in real-time for the trial to proceed.
An integral assay that will be used to determine eligibility or treatment may need to be performed under an Investigational
Device Exemption (IDE) from the FDA.
Integrated biomarkers are defined as tests that are designed to test a hypothesis, not to generate hypotheses. The integrated
biomarker assay already should have been tested in human subjects and demonstrated reproducible analytic qualities.
Biomarker Review Committee (BRC) Requirements: With the current emphasis on biomarker-driven drug development, it is
necessary to ensure that fit-for-purpose assays of these biomarkers are incorporated in CTEP-sponsored protocols. To that
end, the NCI Division of Cancer Treatment and Diagnosis (DCTD) has formed the Biomarker Review Committee (BRC), which
is now responsible for reviewing the biomarker components of CTEP-sponsored clinical trials. Specifically, LOIs for trials that
are not reviewed by an NCI disease-specific steering committee will require BRC review and approval if they meet any of the
following criteria:




Integral or integrated biomarkers
CTEP funds are requested for sample collection and/or performance of the assay
Requires biopsies that are mandatory specifically for the purpose of a biomarker assay
Procedure is burdensome on the patient (invasiveness, schedule, etc.)
The BRC may also, at its discretion, review any assay judged to be of particular importance to the trial. To expedite BRC review,
please complete the Study Checklist for CTEP-Supported Early Phase Trials with CTEP-Supported Biomarker Assays
[at: http://ctep.cancer.gov/protocolDevelopment/ancillary_correlatives.htm ] for all assays that meet any of these criteria, and
submit the completed checklist(s) as an appendix to this LOI. In lieu of completing checklist items 5-6, the biomarker assay
templates available at http://www.cancerdiagnosis.nci.nih.gov/diagnostics/templates.htm may be utilized.
(Note: For LOI review, each biomarker assay intended for inclusion in the study must be entered into the table below,
and all fields must be completed, regardless of whether BRC review will be needed.)
Biomarkers Table*
Biomarker Namea
AND Lead PI and Site
Assay
(CLIA: Y/N)
Use (Integral, Integrated, or
Exploratory)AND Purpose b
Tissue/Body Fluid Tested
and Timing of Assay
[Click and enter
Biomarker(s)]
[Click and enter
Assay]
[Click and enter Use]
[Click and enter
Tissue/Fluid]
[Click and enter Lead
PI/Site]
CLIA:
[Click and enter
Biomarker(s)]
[Click and enter
Assay]
[Click and enter Lead
PI/Site]
CLIA:
[Click and enter
Biomarker(s)]
[Click and enter
Assay]
[Click and enter Lead
PI/Site]
CLIA:
[Click and enter
Biomarker(s)]
[Click and enter
Assay]
[Click and enter Lead
PI/Site]
CLIA:
[Click and enter Purpose]
[Click and enter Timing]
[Click and enter Use]
[Click and enter Purpose]
[Click and enter
Tissue/Fluid]
[Click and enter Timing]
[Click and enter Use]
[Click and enter Purpose]
[Click and enter
Tissue/Fluid]
[Click and enter Timing]
[Click and enter Use]
[Click and enter Purpose]
[Click and enter
Tissue/Fluid]
[Click and enter Timing]
M/O
Funding
Source(s) c
[Click and
enter Funding
Source]
[Click and
enter Funding
Source]
[Click and
enter Funding
Source]
[Click and
enter Funding
Source]
* Insert additional rows as needed.
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LOI Submission Form
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a
Multiple biomarkers may be listed in the same row if they are performed using the same assay in the same laboratory by the
same investigator. This field may also specify a panel (e.g., BROCA); individual markers in the panel may be listed in Appendix
B.
b
Briefly specify the role of the biomarker in the study (e.g., eligibility criterion, assignment to treatment, stratification factor,
response assessment, prospective research, hypothesis generation, etc.). If a hypothesis will be tested, please succinctly state
it (e.g., “to identify biomarkers of response”).
c
Indicate all funding sources. Specify whether CTEP support is requested for the sample (tissue/fluid) collection, for the assay,
or both.
Imaging Correlates Table*
Correlative Objective
(Name of Correlate & Lead PI and
Site)
Imaging Technique
Organ(s) Scanned and Timing of Scans
M/O
* Insert additional rows as needed
Endpoints/Statistical Considerations: (State explicitly the null and alternative hypothesis(es) for the primary objective(s).
Also state the sample size and associated type I and type II errors. Provide an analysis plan for both primary and secondary
objectives, including correlatives. Include information about which statistical tests will be applied. State the projected accrual
rate and ensure that the accrual goals are realistic and achievable with current resources.)
[Click and enter Endpoints]
References: (Provide references for cited data and key background/concepts. Verify all references.)
[Click and enter References]
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LOI Submission Form
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Appendix A – Documentation for Projected Accrual & Competing Trials
Projected Accrual: Projected accrual rates should be realistic. Actual accrual will be monitored and measured against this
accrual estimate and failure to meet accrual goals may result in study closure.
Note: Failure to provide sufficient information for NCI reviewers to evaluate the ability to attain projected accrual may
delay approval of the LOI.
Overall Study Projected Accrual Table
Total Projected Accrual
[Click and enter Number]
Projected Start Date
[Enter Month] / [Enter Year]
Projected End Date
[Enter Month] / [Enter Year]
Note: For ETCTN or multi-institutional phase 2 or phase 1/2 studies, please fill out the Site-specific Projected Accrual Table
below. Include all participating institutions, each in a separate row. (Note: the Site-specific Projected Accrual Table does not
apply to single institution studies or studies led by an NCTN organization.)
Site-specific Projected Accrual Table
Institution Name
Projected Accrual
[Click and enter
Relevant Site Name]
[Click and enter
Number]
Documentation for Projected Accrual (Last 3 Years): To document accrual rate, list trials with similar patient populations,
Phase, and Prior Therapy; include all relevant trials with a status of Active within the last 3 years. Only include patients enrolled
at site(s) relevant to the LOI proposal. To provide data on additional trials, insert additional rows as needed.
Note: This information is required for LOI proposals including a CTEP-IND agent. For NCTN-led or single institution studies,
enter total trial documented accrual information. For ETCTN or multi-institutional phase 2 or phase 1/2 studies, enter both total
trial documented accrual information and then enter site-specific information separately below total trial accrual; you only need
to supply site-specific accrual information for sites that will be participating in the proposed trial.
Documented Accrual Table*
Protocol Number / Title / Sponsor/ Trial Lead Institution or Group (Include NCI Number if NCI-sponsored; include overall
trial accrual information below)
Protocol Number
Accrual Start
Date
Temporary
Accrual
Closure
Final Accrual
Date
Accrual/Month
Rate (excluding
temporary closure
period)
No. of Patients
Enrolled
[Click and enter
Protocol Number]
[Click and enter
Accrual Start Date]
[Click and enter
Temporary
Closure Dates]
[Click and enter
Closed to Accrual
Date or current
date if still
accruing patients]
[Provide
Accrual/Month rate
for trial excluding
temporary closure
period]
[Click and enter
Total Trial Accrual
Number]
Protocol (Number the same as above) Site-specific accrual information (indicate information for LOI relevant sites)
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LOI Submission Form
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Protocol Number
Accrual start
Date
Temporary
accrual
closure
Final Accrual
Date
Accrual/Month
Rate (excluding
temporary closure
period)
No. of Patients
Enrolled
[Click and enter
Protocol Number] /
[Click and enter
Relevant Site
Name]
[Click and enter
Accrual Start Date]
[Click and enter
Temporary
Closure Dates]
[Click and enter
Closed to Accrual
Date or current
date if still
accruing patients]
[Provide
Accrual/Month rate
for site excluding
temporary closure
period]
[Click and enter
Site-Specific
Accrual Number]
[Click and enter
Protocol Number] /
[Click and enter
Relevant Site
Name]
[Click and enter
Accrual Start Date]
[Click and enter
Temporary
Closure Dates]
[Click and enter
Closed to Accrual
Date or current
date if still
accruing patients]
[Provide
Accrual/Month rate
for site excluding
temporary closure
period]
[Click and enter
Site-Specific
Accrual Number]
[Click and enter
Protocol Number] /
[Click and enter
Relevant Site
Name]
[Click and enter
Accrual Start Date]
[Click and enter
Temporary
Closure Dates]
[Click and enter
Closed to Accrual
Date or current
date if still
accruing patients]
[Provide
Accrual/Month rate
for site excluding
temporary closure
period]
[Click and enter
Site-Specific
Accrual Number]
[Click and enter
[Click and enter
[Click and enter [Click and enter
[Provide
Protocol Number] / Accrual Start Date] Temporary
Closed to Accrual Accrual/Month rate
[Click and enter
Closure Dates]
Date or current
for site excluding
Relevant Site
date if still
temporary closure
Name]
accruing patients] period]
* Insert additional groups of rows for total trial accrual and site-specific accrual as needed.
[Click and enter
Site-Specific
Accrual Number]
Competing Trials: List all Active, Approved, or In Review studies at your institution for which this patient population will be
eligible (active trials should also be listed under documented accrual). To provide data on additional trials, insert additional rows
as needed.
Competing Trials Table*
Protocol Number /
Title / Sponsor/
Relevant Site only
Trial Activation Date
Anticipated
Completion Date
(Include NCI Number if
NCI-sponsored)
[Click and enter
[Click and enter
Number] / [Click and
Activation Date]
enter Title] / [Click and
enter Sponsor / [Click
and enter Relevant
Site Name]]
* Insert additional rows as needed.
No. of Patients Enrolled to Date / Patient
Enrollment Period /
Duration of Patient Enrollment /
Total planned Patient Enrollment
(Only include patients enrolled at site(s) relevant
to LOI proposal.)
[Click and enter
Anticipated
Completion Date]
[Click and enter Patients Enrolled] /
[Click and enter Enrollment Start Date] to [Click
and enter Enrollment End Date] /
[Click and enter the Number of Months of
Enrollment] /
[Click and enter Planned Enrollment]
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LOI Submission Form
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Appendix B – Correlative and Biomarker Assay Description(s)
Details of biomarker assays may be provided here.
For all integral and integrated biomarkers and for any exploratory biomarkers for which CTEP support is requested for sample
collection or performance of the assay, state experience with the assay and assay methods, performance, operating
characteristics, and whether the assay will be performed in a CLIA-approved laboratory. Please use the Study Checklist for
CTEP-Supported Early Phase Trials with CTEP-Supported Biomarker Assays at:
http://ctep.cancer.gov/protocolDevelopment/ancillary_correlatives.htm. In lieu of completing checklist items 5-6, the biomarker
assay templates available at http://www.cancerdiagnosis.nci.nih.gov/diagnostics/templates.htm may be utilized.
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LOI Submission Form
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